Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults

Abstract

Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of >40 kg/m 2 ) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m 2 ) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (C max ) and area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (P > 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (V z ) (P ‫؍‬ 0.110) and clearance (CL) values (P ‫؍‬ 0.214) were comparable between groups. Nearly identical (P ‫؍‬ 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid V z and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC 0 -ؕ values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.) M ore than one-third of the U.S. adult population is classified as obese, based on having a body mass index (BMI) of Ն30 kg/m 2 (1). Acute bacterial skin and skin structure infections (ABSSSI) are common in obese patients, who are predisposed to developing type 2 diabetes (2). Tedizolid is a novel oncedaily oxazolidinone that was recently approved for the treatment of ABSSSI at 200 mg daily for 6 days. Tedizolid is a more potent oxazolidinone than linezolid, and it does not interact with selective serotonin reuptake inhibitors (SSRIs). This pharmacological difference is significant because the use of antidepressants is higher among obese adults than among nonobese adults in the United States (3, 4). As a consequence, tedizolid may be selected over linezolid for the treatment of ABSSSI in obese patients, who are potentially managed with SSRIs. To date, population pharmacokinetic (POP-PK) analyses have demonstrated that the concentration-time profiles of tedizolid are similar for subjects with class II obesity (BMI of Ն35 kg/m 2 ) and nonobese adults (BMI of Ͻ30 kg/m 2 ), suggesting that no dose modification for body size is necessary (5). In ...

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

“…Pooled analyses of phase III studies showed a numerical, but nonsignificant, decrease in clinical response rates with increasing BMIs. 70 No dose adjustments for tedizolid are expected for obesity based on two analyses showing similar PK profiles (AUC, Vd, Cl, and C max ) in obese versus nonobese healthy adults and those with skin and skin structure infections. 70,71 Summary Oxazolidinones do not appear to require dose adjustments in obesity.…”

“…70 No dose adjustments for tedizolid are expected for obesity based on two analyses showing similar PK profiles (AUC, Vd, Cl, and C max ) in obese versus nonobese healthy adults and those with skin and skin structure infections. 70,71 Summary Oxazolidinones do not appear to require dose adjustments in obesity. Data are insufficient at this time to recommend alternative linezolid dosing strategies (e.g., continuous infusions) in obese populations but should be studied in higher degrees of obesity (e.g., above 150 kg), for the treatment of VAP and those with concomitant critical illness.…”

Pharmacokinetics of Tedizolid in Obese and Nonobese Subjects

“…Further evidence is provided by a recently published study demonstrating that the PK exposure was similar (ß20% lower) in morbidly obese (BMI ࣙ 40 kg/m 2 ) and in nonobese subjects, although it should be noted that this was a small-scale study with just 9 subjects per group. 25 In the 2 phase 3 studies of tedizolid in patients with ABSSSIs, the early clinical response at 48 to 72 hours declined with increasing BMI in tedizolid-treated patients. 26 However, by the posttherapy evaluation, investigator-assessed clinical success rates were similar for patients with BMI < 30 and ࣙ 30 kg/m 2 (94.6% and 91.1%, respectively) and were slightly lower for the group with BMI ࣙ 35 kg/m 2 (86.0%; data on file).…”

Anti-infective Dosing for Obese Adult Patients: A Focus on Newer Drugs to Treat Methicillin-resistant Staphylococcus aureus Acute Bacterial Skin and Skin Structure Infections

“…76 A recent independent study confirmed that the tedizolid plasma PK profile is not significantly different in morbidly obese subjects compared with age-, sex-, and IBW-matched nonobese subjects. 77 These findings are relevant because lower numerical but nonsignificant trends in response rates were observed as a function of increasing BMI category in the pooled analyses of Phase III studies of tedizolid. 78 Despite these trends, insufficient evidence currently exists to recommend a higher daily dose of tedizolid in obese patients.…”